Allogeneic bone marrow transplantation offers curative therapy for patients with leukemia and other diseases. However, transplant-related complications, like chronic graft-versus-host disease (GVHD) result in significant morbidity and mortality. Chronic GVHD results from donor lymphocytes reacting to tissues of the bone marrow recipient (alloreactivity). Standard treatment of chronic GVHD includes prednisone alone or in combination with cyclosporine. Complete resolution of extensive chronic GVHD occurs in only 30-40 percent of patients treated with standard therapy. The proposed study will examine the benefit of adding hydroxychloroquine (HCQ) to standard therapy for the treatment of newly diagnosed extensive chronic GVHD. The study will be conducted as a randomized, placebo-controlled, double-blinded Phase III trial under the auspices of The Children's Cancer Group. This study will be the first large cooperative group trial of therapy for chronic GVHD. The trial will include laboratory studies to improve our understanding of the biology of GVHD. A better understanding of the factors involved in GVHD will allow the development of targeted therapies for GVHD in the future. HCQ inhibits alloreactivity in vitro. Mechanisms of action of HCQ include interference with antigen processing and presentation, reduction of cytokine production, inhibition of cytotoxicity, and interference with T cell signal transduction. HCQ can prevent acute and chronic GVHD in murine models. A recently completed Phase II trial of HCQ for the treatment of patients with steroid-resistant or steroid-dependent chronic GFHD, or who were experiencing toxicity from other immunosuppressive drugs needed to control their GVHD, showed that HCQ had activity for chronic GVHD. Thirty-eight patients were enrolled. 55 percent of 29 evaluable patients with chronic GVHD had a response. No significant toxicity was seen. HCQ is a well-tolerated drug with activity in chronic GVHD, and with non-overlapping toxicities with other immunosuppressive drugs. The proposed study will evaluate the efficacy of a treatment regimen of hydroxychloroquine, cyclosporine, and alternate-day prednisone compared to the standard regimen of cyclosporine and alternate-day prednisone for newly diagnosed extensive chronic GVHD. Patients will be randomized to one of the two regimens and will receive nine months of therapy. Patients will be followed to determine their response to therapy, degree of disability, and survival. Blood from patients will be examined at study entry and then every three months to examine the biology of chronic GVHD, and to see if the different treatment regimens affect the immune system differently.
